Not applicable.
This invention relates to derivatized carbohydrates, compositions comprised thereof and methods for their use. The derivatized carbohydrates can be used to form solid delivery systems useful for the dissolution, encapsulation, storage and delivery of a variety of therapeutic and diagnostic molecules.
Solid delivery systems are useful in a wide variety of applications such as controlled release of labile molecules, particularly bioactive materials such as organic pharmaceutical compounds, enzymes., vaccines and biological control agents such as pesticides and pheromones.
Drugs and other biologically active agents are frequently administered orally by means of solid dosage forms, such as tablets and capsules. Other oral solid dosage forms include lozenges and other hard candies. Solid dosage forms can also be implanted, such as subcutaneously for drug delivery. Additionally, solid dosage forms can be delivered intravenously, or by inhalation to the pulmonary system.
Solid dose delivery of bioactive materials to biological tissues such as mucosal, dermal, ocular, subcutaneous, intramuscular, intradermal and pulmonary offers several advantages over methods such as hypodermic injection and transdermal administration via so-called xe2x80x9cpatchesxe2x80x9d. Using injection, there is a risk of infection using conventional needles and syringes. Dosing using multidose vials is sometimes variable, and physical discomfort often attends hypodermic injection. Devices used for administering drugs transdermally usually comprise a reservoir layer of drug and a laminated composite which adheres to the skin, i.e., transdermal patches, such as described in U.S. Pat. No. 4,906,463. Many drugs can not be effectively delivered transdermally, nor have transdermal drug release rates for those capable of such delivery been perfected. Additionally, transdermal patches often cause topical reactions, in many instances precluding their long-term use.
Subdermal implantable therapeutic systems have been formulated for slow release of certain pharmaceutical agents for extended periods of time such as months or years. A well-known example is the Norplant(copyright) implant for delivery of steroid hormones. In membrane permeation-type controlled drug delivery, the drug is encapsulated within a compartment enclosed by a rate-limiting polymeric membrane. The drug reservoir can contain either drug particles or a dispersion (or solution) of solid drug in a liquid or a solid type dispersing medium. The polymeric membrane can be fabricated from a homogeneous or a heterogeneous nonporous polymeric material or a microporous or semipermeable membrane. The encapsulation of the drug reservoir inside the polymeric membrane can be accomplished by molding, encapsulation, microencapsulation, or other techniques.
The implants release drugs by dissolution of the drug in the inner core and slow release across the outer matrix. The drug release from this type of implantable therapeutic system is dependent on drug dissolution rate in the polymeric membrane, often causing a biphasic release rate. The inner core substantially dissolves; however, generally, the outer matrix does not dissolve.
Implants are placed subcutaneously by making an incision in the skin and forcing the implants between the skin and the muscle. At the end of their use, if not dissolved, these implants must be surgically removed. U.S. Pat. No. 4,244,949 describes an implant which has an outer matrix of an inert plastic such as polytetrafluoroethylene resin.
Other implantable therapeutic systems involve matrix diffusion-type controlled drug delivery. The drug reservoir is formed by the homogeneous dispersion of drug particles throughout a lipophilic or hydrophilic polymer matrix. The dispersion of drug particles in the polymer matrix is accomplished by blending the drug with a viscous liquid polymer or a semisolid polymer at room temperature, followed by cross-linking of the polymer, or by mixing the drug particles with a melted polymer at an elevated temperature. The drug reservoir can also be fabricated by dissolving the drug particles and/or the polymer in an organic solvent followed by mixing and evaporation of the solvent in a mold at an elevated temperature or under vacuum. The rate of drug release from this type of delivery device is generally not constant. An example of this type of implantable therapeutic system is the Compudose implant.
A variety of formulations have been provided for administration in aerosolized form to mucosal surfaces, particularly xe2x80x9cby-inhalationxe2x80x9d (naso-pharyngeal and pulmonary). Compositions for by-inhalation pharmaceutical administration generally comprise a liquid formulation of the pharmaceutical agent and a device for delivering the liquid in aerosolized form. U.S. Pat. No. 5,011,678 describes suitable compositions containing a pharmaceutically active substance, a biocompatible amphiphilic steroid and a biocompatible (hydro/fluoro) carbon propellant. U.S. Pat. No. 5,006,343 describes suitable compositions containing liposomes, pharmaceutically active substances and an amount of alveolar surfactant protein effective to enhance transport of the liposomes across a pulmonary surface. U.S. Pat. No. 5,608,647 describes methods for administering controlled amounts of aerosol medication from a valved canister.
One drawback to the use of aerosolized formulations is that maintenance of pharmaceutical agents in aqueous suspensions or solutions can lead to aggregation and loss of activity and bioavailability. The loss of activity can be partially prevented by refrigeration; however, this limits the utility of these formulations. The use of powdered formulations overcomes many of these drawbacks. The requisite particle size of such powders is 0.5-5 microns in order to attain deep alveolar deposition in pulmonary delivery. Unfortunately, powders of such particle size tend to absorb water and clump, thus diminishing deposition of the powder in the deep alveolar spaces. PCT GB95/01861 described powders suitable for use in by-inhalation delivery. The powders are of uniform particle size and can be produced with varying degrees of hydrophobicity to reduce clumping and increase drug release in the surfactant environment of the lung.
Solid dose delivery vehicles for ballistic, transdermal administration have also been developed. For example, in U.S. Pat. No. 3,948,263, a ballistic animal implant comprised of an exterior polymeric shell encasing a bioactive material is described for veterinary uses. Similarly, in U.S. Pat. No. 4,326,524, a solid dose ballistic projectile comprising bioactive material and inert binder without an exterior casing is disclosed. Delivery is by compressed gas or explosion. Ballistic delivery at the cellular level has also been successful. Klein (1987) Nature, 327:70-73. There are few existing formulations suitable for ballistic delivery. Powder formulations of pharmaceuticals generally used are unsuitable for ballistic administration, because they vary in size, shape and density. The particles described in PCT GB95/01861 are useful for ballistic delivery due to their discrete size.
For drug delivery, it is advantageous to provide solid drug delivery systems of defined size, shape, density and dissolution rate. It is also advantageous to provide solid drug delivery systems that are capable of sustained, controlled release of the drug. It is further advantageous to provide solid dose delivery systems that can be formulated using simple and economical methods.
PCT/GB 90/00497 describes slow release glassy systems for formation of implantable devices. The described implants are bioabsorbable and need not be surgically removed. However, these devices are severely limited in the type of bioactive material that can be incorporated as these must be stable to heat and/or solvent to enable incorporation into the delivery device. PCT WO 93/10758 describes a carbohydrate glass matrix for the sustained release of a therapeutic agent, which includes a carbohydrate, a therapeutic agent, an agent that inhibits recrystallization of the matrix, and a water insoluble wax which modifies release of the therapeutic agent from the matrix.
PCT WO 96/03978 describes solid dose delivery systems, which include a vitreous vehicle loaded with a bioactive substance, and which are capable of releasing the substance at a controlled rate. The controlled release is achieved by the use of glass-forming, hydrophobically derivatized carbohydrates as solid vehicles, with the choice of derivative group selected to reduce solubility of the matrix material in aqueous media.
All references cited herein are hereby incorporated herein by reference.
Derivatized carbohydrates are provided, as well as compositions comprised thereof and methods of use thereof. The derivatized carbohydrates are generally polyol carbohydrates, wherein at least a portion of the hydroxyl groups on the carbohydrate are substituted with a branched hydrophobic chain, such as a hydrocarbon chain, via, for example, an ether or ester linkage. The derivatized carbohydrates are in one embodiment oligosaccharide ester derivatives, such as ester derivatives of disaccharides.
The derivatized carbohydrates can be formed by modification of carbohydrates. Suitable carbohydrates include, but are not limited to, glucose, lactose, cellobiose, sucrose, trehalose, raffinose, melezitose and stachyose. The hydroxyl groups of the carbohydrate can be substituted, for example via ester or ether linkages, with a branched hydrocarbon chain, such as a C3 to C30 branched hydrocarbon chain. The branched hydrocarbon chain can be a C3 to C30 hydrocarbon chain, for example, a C3 to about a C20 hydrocarbon chain. In a preferred embodiment, the hydrocarbon chain includes about a C3 to C8 hydrocarbon chain. The carbohydrate can be substituted, for example, by esterification of one or more of the hydroxyl groups on the carbohydrate with an acid such as a fatty acid including a branched hydrocarbon chain. Mixed esters and ethers of acids including a branched hydrocarbon chain can be formed, e.g., isobutyrate, pivalate, 2,2-dimethylbutyrate, 3,3-dimethylbutyrate, and 2-ethyl butyrate. Optionally, one or more of the remaining hydroxyl groups can be substituted via an ester bond with an acid such as acetate, propionate, or butyrate.
In one embodiment, the substituted carbohydrate can be substituted trehalose (Formula 1) substituted sucrose (Formula 2), substituted lactose (Formula 3), or substituted cellobiose (Formula 4), as shown below. Both xcex1 and xcex2 anomers and mixtures thereof are encompassed by the invention. 
In each of Formulas 1-4, one or more of R1-8 are independently NHR9, N(R9)2, O(Cxe2x95x90O)R9, or OR9, wherein R9 is a branched, saturated or unsaturated, C3-C20 hydrocarbon, e.g., a C3-C8 hydrocarbon, and preferably a C5-C6 hydrocarbon. O(Cxe2x95x90O)R9 can be, for example, an acid acyl group of an acid such as isobutyrate, pivalate, 2,2-dimethylbutyrate, 3,3-dimethylbutyrate, 2-ethyl butyrate. In each of Formula 1-4, the remainder of R1-8 are independently OH, NHR10, N(R10)2, O(Cxe2x95x90O)R10, or OR10, wherein R10 is alkyl, for example a C1-C4 alkyl group, such as methyl, butyl, or propyl.
Preferred derivatized carbohydrates include trehalose hexa-3,3-dimethylbutyrate, trehalose diacetate-hexa-3,3-dimethylbutyrate, trehalose octa-3,3-dimethylbutyrate, lactose isobutyrate-heptaacetate, lactose 3-acetyl-hepta-3,3-dimethylbutyrate and lactose octa-3,3-dimethylbutyrate.
Derivatized carbohydrates within the scope of the invention further include carbohydrates, such as disaccharides, wherein one or more of the free hydroxyl groups are derivatized, for example into an amine or sulfur group, to which hydrophobic branched hydrocarbon chains can be attached, for example, via an amide or thiol linkage.
Compositions, such as delivery systems, comprising the derivatized carbohydrates, and other components such as bioactive agents, carbohydrates, lipids, surfactants, binders, and any other constituents suitable for use in drug delivery are also encompassed by the invention. A wide variety of compositions can be incorporated into the compositions including diagnostic, therapeutic, prophylactic and other biologically active agents. The compositions can be in a vitreous or crystalline form, or mixtures thereof.
Solid dose delivery systems including a substituted carbohydrate can have incorporated therein a substance capable of being released from the solid delivery system. In a preferred embodiment, the solid dose delivery system comprises the substituted carbohydrate in the form of a vitreous glass matrix having the substance incorporated therein. Advantageously., drugs and bioactive agents are thereby provided in a solid, non-hygroscopic, glassy matrix, which undergoes a controlled, surface-led devitrification when immersed in aqueous environments and subsequently effects a sustained release of drugs therein.
Properties of the glassy matrix, such as the release rate of the substance, can be modulated by choice of modified carbohydrate, and other incorporated materials. The glass matrix can be modified, for example, by the addition of different glass formers with known release rates. Other materials can be incorporated into the glass matrix during processing to modify the properties of the final composition, including physiologically acceptable glass formers such as carboxylate, nitrate, sulfate, bisulfate, and combinations thereof. The delivery systems can further incorporate any other suitable carbohydrate and/or hydrophobic carbohydrate derivative, such as glucose pentaacetate or trehalose octaatacetate.
The delivery systems can be in any of a variety of forms including a lozenge, tablet, disc, film, suppository, needle, microneedle, microfiber, particle, microparticle, sphere, microsphere, powder, or an implantable device.
The invention further encompasses methods of making the delivery systems. In one embodiment, the method comprises forming or obtaining a substituted carbohydrate capable of forming a vitreous glass; processing the substituted carbohydrate and a substance to be released therefrom; and forming a solid matrix having the substance incorporated therein.
The processing step can be implemented by melting the substituted carbohydrate and incorporating the substance in the melt, at a temperature sufficient to fluidize the substituted carbohydrate, and insufficient to substantially inactivate the substance, and then quenching the melt. The melt can be processed into a variety of forms. The processing step can be also implemented by dissolving or suspending the substituted carbohydrate and the substance in a solvent effective in dissolving at least one of the derivatized carbohydrates and the substance, and evaporating the solvent.
The invention also encompasses methods of delivering bioactive materials by providing the delivery systems described above and administering the system to a biological tissue. Administration can be by any suitable means including mucosal, oral, topical, subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous and by-inhalation.
The delivery systems are uniquely suited to delivery of hydrophobic substances such as pesticides, pheromones, steroid hormones, peptides, peptide mimetics, antibiotics and other organic pharmaceuticals such as synthetic corticosteroids, bronchodilators, immumodulators and immunosuppressants. The invention encompasses these delivery systems. The delivery systems are also suitable for delivery of a wide variety of non-medical substances, such as compounds used in agricultural applications, including pesticides, enzymes or other substances added to laundry detergents; and dyes or colorants.